Allopurinol and Endothelial Function: A Systematic Review with Meta-analysis of Randomized Controlled Trials

Overview

Journal Cardiovasc Ther

Publisher Hindawi

Date 2018 Apr 20

PMID 29673103

Citations 29

Authors

Manal M Alem

Affiliations

Soon will be listed here.

Abstract

Aim: Oxidative stress and endothelial dysfunction are two inter-related conditions commonly seen in patients with cardiovascular risk factors. The enzyme, xanthine oxidase, is an important contributor to these phenomena but to a variable degree in different patient populations. This meta-analysis will summarize the effect of allopurinol, an established xanthine oxidase inhibitor, on endothelial function among patients with different comorbidities.

Methods: Medline Complete, PubMed, ProQuest, ClinicalKey, Wiley Online Library, and Cochrane Central Register of Controlled Trials were searched till July 29, 2017. Meta-analysis was planned for randomized controlled trials (RCTs) that investigated allopurinol effects on endothelial function. A random effect model was used to calculate the standardized mean difference (with 95% confidence intervals: CI) as an estimate of effect size. Heterogeneity was quantified by four types of information: Q statistics, I statistic, Tau-squared (T ), and Tau (T).

Results: Thirty eligible studies were identified; 12 were included in the final analysis and subdivided among 3 patient's groups: patients with chronic heart failure (CHF; 197 patients), patients with chronic kidney disease (CKD; 183 patients), and patients with type 2 diabetes mellitus (DM; 170 patients). Allopurinol was found to have a statistically significant benefit on endothelial function in patients with CHF and CKD but not in type 2 DM. The standardized mean differences and CI in the three patient's groups were 0.776 (0.429, 1.122), 0.350 (0.009, 0.690), and 1.331 (-0.781, 3.444), respectively.

Conclusion: Allopurinol has an antioxidant property that might partially reverse endothelial dysfunction in patients with certain comorbidities. The importance of this property and the magnitude of the beneficial effect are likely to be related to the relative contribution of xanthine oxidase into the oxidative stress associated with different underlying pathologies.

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References

Kuppusamy U, Indran M, Rokiah P . Glycaemic control in relation to xanthine oxidase and antioxidant indices in Malaysian Type 2 diabetes patients. Diabet Med. 2005; 22(10):1343-6. DOI: 10.1111/j.1464-5491.2005.01630.x. View

Tousoulis D, Andreou I, Tsiatas M, Miliou A, Tentolouris C, Siasos G . Effects of rosuvastatin and allopurinol on circulating endothelial progenitor cells in patients with congestive heart failure: the impact of inflammatory process and oxidative stress. Atherosclerosis. 2010; 214(1):151-7. DOI: 10.1016/j.atherosclerosis.2010.11.002. View

Farquharson C, Butler R, Hill A, Belch J, Struthers A . Allopurinol improves endothelial dysfunction in chronic heart failure. Circulation. 2002; 106(2):221-6. DOI: 10.1161/01.cir.0000022140.61460.1d. View

Kao M, Ang D, Gandy S, Nadir M, Houston J, Lang C . Allopurinol benefits left ventricular mass and endothelial dysfunction in chronic kidney disease. J Am Soc Nephrol. 2011; 22(7):1382-9. PMC: 3137586. DOI: 10.1681/ASN.2010111185. View

Kok V, Horng J, Chang W, Hong Y, Chang T . Allopurinol therapy in gout patients does not associate with beneficial cardiovascular outcomes: a population-based matched-cohort study. PLoS One. 2014; 9(6):e99102. PMC: 4045898. DOI: 10.1371/journal.pone.0099102. View

Kato M, Hisatome I, Tomikura Y, Kotani K, Kinugawa T, Ogino K . Status of endothelial dependent vasodilation in patients with hyperuricemia. Am J Cardiol. 2005; 96(11):1576-8. DOI: 10.1016/j.amjcard.2005.07.068. View

Murase T, Nampei M, Oka M, Miyachi A, Nakamura T . A highly sensitive assay of human plasma xanthine oxidoreductase activity using stable isotope-labeled xanthine and LC/TQMS. J Chromatogr B Analyt Technol Biomed Life Sci. 2016; 1039:51-58. DOI: 10.1016/j.jchromb.2016.10.033. View

Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T . Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation. 2001; 104(22):2673-8. DOI: 10.1161/hc4601.099485. View

Schmidt R, Baylis C . Total nitric oxide production is low in patients with chronic renal disease. Kidney Int. 2000; 58(3):1261-6. PMC: 2745260. DOI: 10.1046/j.1523-1755.2000.00281.x. View

10.

Raitakari O, Celermajer D . Flow-mediated dilatation. Br J Clin Pharmacol. 2000; 50(5):397-404. PMC: 2014404. DOI: 10.1046/j.1365-2125.2000.00277.x. View

11.

Jalal D, Decker E, Perrenoud L, Nowak K, Bispham N, Mehta T . Vascular Function and Uric Acid-Lowering in Stage 3 CKD. J Am Soc Nephrol. 2016; 28(3):943-952. PMC: 5328166. DOI: 10.1681/ASN.2016050521. View

12.

Hassoun P, Yu F, Cote C, Zulueta J, Sawhney R, Skinner K . Upregulation of xanthine oxidase by lipopolysaccharide, interleukin-1, and hypoxia. Role in acute lung injury. Am J Respir Crit Care Med. 1998; 158(1):299-305. DOI: 10.1164/ajrccm.158.1.9709116. View

13.

Dogan A, Yarlioglues M, Gungor Kaya M, Karadag Z, Dogan S, Ardic I . Effect of long-term and high-dose allopurinol therapy on endothelial function in normotensive diabetic patients. Blood Press. 2010; 20(3):182-7. DOI: 10.3109/08037051.2010.538977. View

14.

George J, Carr E, Davies J, Belch J, Struthers A . High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation. 2006; 114(23):2508-16. DOI: 10.1161/CIRCULATIONAHA.106.651117. View

15.

Davey J, Turner R, Clarke M, Higgins J . Characteristics of meta-analyses and their component studies in the Cochrane Database of Systematic Reviews: a cross-sectional, descriptive analysis. BMC Med Res Methodol. 2011; 11:160. PMC: 3247075. DOI: 10.1186/1471-2288-11-160. View

16.

Tsutsui T, Tsutamoto T, Wada A, Maeda K, Mabuchi N, Hayashi M . Plasma oxidized low-density lipoprotein as a prognostic predictor in patients with chronic congestive heart failure. J Am Coll Cardiol. 2002; 39(6):957-62. DOI: 10.1016/s0735-1097(02)01721-7. View

17.

Butler R, Morris A, Belch J, Hill A, Struthers A . Allopurinol normalizes endothelial dysfunction in type 2 diabetics with mild hypertension. Hypertension. 2000; 35(3):746-51. DOI: 10.1161/01.hyp.35.3.746. View

18.

Miric D, Kisic B, Filipovic-Danic S, Grbic R, Dragojevic I, Miric M . Xanthine Oxidase Activity in Type 2 Diabetes Mellitus Patients with and without Diabetic Peripheral Neuropathy. J Diabetes Res. 2016; 2016:4370490. PMC: 5124663. DOI: 10.1155/2016/4370490. View

19.

Alem M . Allopurinol and endothelial function: A systematic review with meta-analysis of randomized controlled trials. Cardiovasc Ther. 2018; 36(4):e12432. PMC: 6175067. DOI: 10.1111/1755-5922.12432. View

20.

Doehner W, Schoene N, Rauchhaus M, Leyva-Leon F, Pavitt D, Reaveley D . Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies. Circulation. 2002; 105(22):2619-24. DOI: 10.1161/01.cir.0000017502.58595.ed. View